February 2017

Safety issues with vedolizumab

As mentioned previously in this issue of TreatmentUpdate, an important study in monkeys has inspired an American clinical trial in people with HIV with the drug vedolizumab. This is an antibody designed for use in people. Vedolizumab, sold as Entyvio, is given intravenously for the treatment of inflammatory intestinal conditions (such as Crohn’s disease). It is licensed for treating such conditions in Canada, the U.S. and the European Union. As vedolizumab will likely draw much interest for testing with HIV-positive people, it is useful to review the information that has been collected about its safety from well-designed studies.

Vedolizumab

The antibody works by binding, or attaching to, a receptor called a4b7 (alpha4beta7). This receptor helps CD4+ and other cells of the immune system zero in on the pockets of the immune system that are arrayed around the intestines. By blocking this receptor, vedolizumab stops cells of the immune system from migrating to the intestines and enhancing inflammation in people who have Crohn’s (and related) diseases.

The studies

Researchers in Canada, Belgium, the Netherlands, Italy, UK and U.S. collaborated in a review of six clinical trials of vedolizumab. In some of these studies placebos were used. Their review focused on more than 2,800 participants who received the drug between May 2009 and June 2013. About 50% of participants received the drug for one year. However, a minority of participants took the drug for up to five years.

In general, the researchers found that vedolizumab was safe with a low rate of infections and complications occurring. We now summarize the different complications that occurred in the safety review.

Reactions to infusions

Vedolizumab has to be given intravenously. Less than 6% of participants developed adverse effects related to infusion of vedolizumab. The most common of these adverse effects were nausea (14 people) and headache (10 people). These were generally of mild-to-moderate intensity.

Infections

According to the researchers, “We did not observe an overall increase in the risk of infection or serious infection with vedolizumab exposure....” Risk factors for infections appeared to include the use of other drugs such as corticosteroids (which can weaken the immune system) and prescribed narcotics.

Most infections affected the upper lungs, throat or sinuses. These infections, which were described by the researchers as “mild to moderate in severity,” responded to standard therapy. Less than 1% of participants who developed these infections discontinued vedolizumab. Furthermore, these types of infections were more common among people who received placebo. Researchers are not certain why this was the case but they proposed that people who received placebo may have “had more active disease and a greater propensity for intestinal infections, which could confound the reported incidence rates.” They noted that vedolizumab users had a relatively low rate of infections, which was also noted by other researchers who have collected data about the safety of this drug.

There were 15 cases of bacterial intestinal infections (caused by Clostridia), all of which occurred in vedolizumab users.

Unlike some other intravenous treatments for inflammatory conditions, none of the following serious infections occurred in participants who received vedolizumab:

disseminated TB (tuberculosis)

systemic yeast infections

disseminated shingles (herpes zoster)

CMV (cytomegalovirus) infection outside of the digestive tract

PCP (Pneumocystis pneumonia)

PML (progressive multifocal leukoencephalopathy)

Cancers

During placebo-controlled studies, the distribution of cancer cases that occurred were as follows:

vedolizumab – five participants

placebo – one participant

After the placebo-controlled phase of the studies, all participants were offered vedolizumab (this subsequent phase is called “open-label,” where participants are aware of the drug that they are getting). During the open-label phase, an additional 13 participants were diagnosed with cancer.

Thus, a total of 19 people in the studies developed cancer. Since there were 2,830 people whose data were used for the safety analysis, these 19 people who got cancer accounted for 0.67% of participants.

Understanding the risk of cancer

When reading the cancer analysis, it is important to bear in mind that tumours do not suddenly appear overnight but can sometimes take months or years to develop until their presence is detected. All the people who developed cancer in the vedolizumab studies had one or more risk factors for cancer, as follows:

all but one person who developed cancer had previously been exposed to drugs that weakened their immune system. These drugs are often useful for managing serious inflammatory conditions but also increase a person’s risk for cancer.

nearly half of the people who developed cancer had a history of smoking

some participants had a history of cancer prior to receiving vedolizumab

There was no link between the use of vedolizumab and the development of cancer or any link between the number of doses of vedolizumab used and cancer risk.

Of the 19 cases of cancer, most (12) were resolved with treatment. However, in four people cancer was not in remission and three people died from complications due to cancer.

Deaths from causes other than cancer

There were 13 deaths due to complications from severe bacterial infections. Concerning these, the researchers stated:

“All…had worsening of underlying disease, significant co-morbidities and complicated hospital courses that included surgeries in two cases, all of which confounded the assessment of relationship to the study drug.”

Two people who were being treated for depression died because of suicide.

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